【doc】脑损伤后早期前列腺素的变化及消炎痛的干预作用

【doc】脑损伤后早期前列腺素的变化及消炎痛的干预作用 脑损伤后早期前列腺素的变化及消炎痛的 干预作用 Changesofprostaglandininearlybraininjuryand therapeuticeffectofindomethacin? TanYuan—fu.DepartmentofNeurosurgery.FirstAmliatedHospitalof GuangxiMedicalUniversity,Nanning53002l,GuangxiZhuangAu— tonomousRegion,China LiYao—hua,DepartmentofBrainSurgery,ZhongdaHospital,MedicalCollege ofSoutheastUniversity,Nanjing210000,JiangsuProvince,China TanYuan—fu?.Male.HanNationality,Bornin1963inZhuzhouCountv, HunanProvince,China,GraduatedfromHunanMedicalUniversityin1999, Doctor,Professor.Researchdirection:traumaticbraininjury. tyful69@sohu.eom Telephone:+86—77l一5356506 Received:2004—09—04Accepted:2004—11—11(04/SMl Abstract BACKGRoUND:Traumaticbraininjurygeneratesacascadeofarachidonic acidmetaboliceventsthatmainlypresentedbytheincrementofprostaglandin andoxygenfreeradicals.1ndomethacincanpotentlyinhibittheactivitv0f cyclooxygenase,decreasethesynthesisofprostaglandins,andmaydecrease theproductionofoxygenfreeradical,andthusmayattenuatethepathological changesofbraininjury. OBJECTIVE:Toobservethechangesofprostaglandininearlybraininjury andafterindomethacinintervention,soastoexplorethepharmaeologieal mechanismofindomethacin. DESIGN:Arandomizedandcontrolledtrialbasedonexperimentalanimals. SETTING:Departmentofneurosurgeryanddepartmentofcerebralsurgery inauniversityhospital. MATERIALS:ThisstudywascarriedoutattheLaboratory0fNeurosurgery Department,MedicalCollegeofSoutheastUniversitybetweenMarchand September2000.Thirty—sixhybridcatswererandomlydividedint0nornqal controlgroup,braininjurygroupandindomethacininterventiongroup,with 12catsineachgroup. INTERVENTIoNS:Braininjurywassimulatedaccordingt0previouslvre— portedgradingmechanicaltraumaticanimalmodelestablishment;catswith mediumbraininjurywereenrolledinthisstudy.Theultimateeoneentrations ofprostaeyelin(PGl2)andthromboxaneA(TXA2)to6一ket0一 prostadandinFl alpha(6一 keto—PGF~ot)andthromboxaneB2(TXB2)inbrainveinblood.as wellastotalbrainsuperoxidedismutase(SOD)andcerebralwatercontent weremeasured6hoursaftertrauma. MAINOUTCOMEMEASURES:6-keto—PGFIot,TXB2.SOD,andcereb ral watercontent. RESULTS:Both6一 keto—PGFlotandTXB2inbrainveinb100dremarkablv increasedinearlybraininjury[from(0.0574-0.010)g/Lt0(0.264 4-0.126)g/L,from(O.0604-0.012)g/Lto(0.1344-0.048)g/Lrespec. tively】,withtheincrementoftheformerhigherthanthelatter.therati00f TXBJ6一 keto—PGF~otdecreasedfrom1.0524-0.145to0.5454-0.184.and cerebralwatercontentincreasedfrom(77.394-0.36)%to(78.06 4-0.41)%;meanwhile.totalbrainSODsignificantlydecreasedfrom (94.8694-5.418)~kat/gto(54.3684-3.417)~kat/g(P<0.011.In contrasttobraininjurygroup,theconcentrationsof6一 keto.PGFIotandTXB2 inindomethacininterventiongroupsignificantlydecreased. whichweresimilar tothoseofcontrolgroup.butthetotalSODsignificantlyincreasedfrom (54.3684-3.417)p.kat/gto(81.4334-7.268)Ixkat/g(P<0. 01),and watercontentlightlydecreasedwithoutstatisticalsignificance(P>0.1). CONCLUSION:PGl2andTXA2increaseinearlybraininj”ryinexDeri. mentalcatmodel,accompaniedbyfreeradicalsynthesis.resultinginthe exacerbationofbraininjury.Indomethacinmaybehelpfult0relievepost. traumaticsecondarybraininjurybyregulatingtheimbalanceofPGT2/TXA2 anddecreasingtheproductionoffreeradical. TanYF,LiYHChangesofprostaglandininearlybraininjuryandtherapeutice”ecf0f indomethacinZhongguoLinchuangKangfu2005;9f5l:232—4fChinal 【?,?zglckfcam] ?qTRoDUCTIoN Recentresearcheshaveshownthataseriesofpathophysiolo西cal metabolicchangesfollowingtraumaticbraininjurymightplayan importantroleinsecondarybraindamage.Specifically,trau— ma—inducedcascadeofarachidonicacidmetabolicevents,mainly presentedbytheincrementofprostaglandinandoxygenfreeradi— cals.-maybeextremelyimportantll一”.Thisstudywasdesignedto indirectlyobservetheposttraumaticchangesofprostacyclin(PGl2) andthromboxaneA(TXA2)inbrainveinblood,aswellasoxygen freeradicals【theresidualofsuperoxidedismutasefSOD)after assumption】,inordertoinvestigatetheeffectofcyclooxygenase inhibitor—indomethacinontraumaticbraininjury. MATERIALSANDMETHoDS Materials ThisstudywascarriedoutatthelaboratoryofNeurosurgeryDe— partment.MedicalCollegeofEast—SouthUniversitybetweenMarch andSeptember2000.Totally36hybridcats,weighedfrom2.5to 3.5kgwithoutsexlimitation【providedbyJiangshuExperimental AnimalCenter,certificationNo:SCXX(Su)2000—00311wereran— domlydividedintonormalcontrolgroup,braininjurygroupand indomethacininterventiongroup,with12catsineach group.Medianextra?durainjurywassimulatedonexperimentalcats ofinjurygroupandindomethacingroupwithgradingmechanical traumaticdevicef4.. Methods Theanimalswereanaesthetizedbyintramuscularinjectionofke— tamineby30mg/kg,followedbyarterialcatheterandheadfixation, thencranialwindowwasopenedatparietaltoinsertconcussivede. vice.Catswithnormalbreath,BP,intra—cranialpressure,cornearetiex andthenarreflexweregivenconcussiveinsults.Traumaticpeakpres— sureof(0.65-i-0.05)kg/cm.andmorphologicalvarianceof3.5mm wereadoptedtomakeinjuryatleftparietallobereachingtothedeep hemisphere.Intracranialpressure,meanarterialpressure.aswellas breathandnervereflexesweremonitored.CatsininterventiongrouD receivedintravenousinjectionofindomethacin(3mg/kg)atpost. traumatic30minutes,andadditionalhalfdosewereadded3hours laterandthencontinuouslymonitoredfor6hours.Noconcussive insultsweregiveninthenormalcontrolgroupinwhichtheratsre- ceivedtheshamoperations. Specimencollection 6-keto—prostaglandinF1alpha(6-keto.PGFIct)andthromboxaneB2 (TXB2)measurement:2mLbrainveinbloodwasrecruitedfrom theuppersagittalsinus30minutesbeforefinishingexperiment.and thenimmediatelycentrifugedat2000rperminutefor5minutes inasilicictube(bothinjectorandtubewererinsedwithheparin indomethacin).Supernatantswerepreservedat一80?forfol— lowingexaminations. StablecatabolicproductsofPGl2andTXA2:6-keto—PGFlqand TXB2weremeasuredwithIRA.TotalSODdetermination:0.4g braintissuesattheinsultedregionwereobtainedbeforethecats werekilledandthenthesetissueswerepreservedat一30?for theexaminationoftotalSODcontentwithhydroxylamine method.Cerebralwatercontent:Afterexperiment,animalswere killedbylettingbloodfromabdominalartery,soonafterthatthe injuredhemispherewastakenouttomeasurethewetweightwithin 3minuteswiththeaidofanalysisscaleof10thousandDrecision andtheconstantweightafterdesiccationinovenof(105?1)oC for24hours,andthusthecerebralwatercontentcouldbecalcu— wetmethods. latedbydry— Statisticalanalysis:AlldatawerepresentedbyMean?SD.andt-test wasusedforcomparison.P<0.05denotedstatisticalsignificance. Mr.YinfromthestatisticsdepartmentofMedicalC011ege0fEast—S0uth UniversitymadestatisticalanalysiswithSPSS9. 0statisticalsoftware. RESULTS Quantitativeanalysisoftheexperimentalanimals Thirty—sixoutoftotal41catsenteredthefinalanalysis. The0ther fivecatswereexcludedforincompleteinformation0r0thersDeci矗c reasons. Changesofposttraumatic6-keto.PGFlOtandTXB2(Table1) Both6-keto—PGF~ctandTXB2inbrainveinb100dremarkablvincreased after6-hourbraininjury,especiallytheincreaseof6-keto—PGFlq. whichcontributingtothereversalofTXPn/6一keto—PGFlq(P<0.01). Both6-keto—PGF~ctandTXB2inindomethacingroupsignificantlv decreasedincontrasttoinjurygroup(P<0.01),similartothos. ofcontrolgroup.However,6-keto—PGFlqwasfoundevenslightlv lowerthancontrolgroup,resultingintheincreasedratioofTXB2/ 6-keto—PGF~ct,whichwashigherthannormalcontr01sbutwithoutsta— tisticalsignificance(P>0.05),indicatingthatthelevels0fPGl2 andTXA2increased6hoursfollowingbraininj”rywithPGl2in particular,whichcouldbemarkedlyinhibitedbvindomethain. ChangesofcerebralSODaftercerebralinjury TotalcerebralSODsignificantlydecreased6hoursaftertraumafP <0.01).ThelevelofSODinindomethacininterventiongr(Jupwas slightlylowerthanthatofcontrolgroup,butsignificantlyhigherthan thatofinjurygroup(P<0.01),indicatingthatmanvfreeradicals .Pp..”d”posttraumaticbrain.whichcanbeattenuatedbyin— domethacin(Table1). Changesofcerebralwatercontent Brainwatercontentoftraumaticside(injurygroup)increasedat6 hours(P<0.01).Itwasslightlylowerinindomethacinintervention groupwhencomparedwiththatofinjurygroup,butnosignificant differencewasfound(P>0.1),indicatingthathydrocephalus0c. curredaftertraumaandcouldnotbeattenuatedbyindomethaci” (Table1). Changesofintracranialpressure,breathandnerverenexes followingbraininjury Atthemediuminjurylevelinthisstudy,incrementofintracranial pressurewithsignificantdifferencecouldnotbeobservedexceDtfbr „nstantIncrementatposttraumatic15S.Thetimeoftemporarybreath standstillrangedfrom60to120swithreflexinhibltingtime1ess than10minutes. Nosignificantdifferencewasfoundbetweeninjury groupandindomethacininterventiongroup(P>0.5). DISCUSSION PGl2,synthesizedinvascularendotheliumduet0thestipulation0f „ ischemiaandmechanicalforce,haspotentdiastoliceffect0nlocal microvessels.TXA2,synthesizedbyplateletsattributingt0collage— nousfiber,ischemiaandplatletscoagulation,ispotentconstrictor0f localvasculature.BothPGl2andTXA!aresynthesizedbvtheacti— vationofcyclooxygenasepathwayofphopholipid—phopholipase A2一arachidonicacidmetabolism,whichisaccompaniedbvfreerad— icalproduction”引.Normally,theratioofPGl2/TXA2keeDsata relativelystablelevelandcanbeadjustedtoregulatelocalcircula— tionthatfitforcerebr~metabolism.Acascade0fAA—+PGs metaboliceventsaregeneratedinbraininjuryduetoactivatedmi— crovascularendothelium,inadditionwithprimary ,injuryofner_vous tissueandcleavageofcellularwallphospholipidintoAA.Because0f differentinducementandsynthesizingsites,inequableproduction0f PGl2andTXA2mayleadtotheimbalanceofPGl2/TXA2atlocal cerebraandsubsequentlylocalbloodflowdisorder. Bloodf10wmav IncreaseduetothediastoliceffectofPGl2ifPGl2ishigherthan TXA2…,butifbloodflowexceedsthedemand0fcerebral metabolism,suchsecondaryoverperfusionmay:Q)induceandag— gravatefreeradicalimpairment;?causeover—perfusionalinjurv:? Increaseintracranlalpressureduetohighercerebralbl【J(Jdf10w:? aggravatecerebralangioedemaduetohighermicrovascularDeiTne— ability?Unthecontrary,ifTXA2exceedsPGl2duetoalargenumber ofendotheliumcellsbreakageinprimaryorsecondaryinjury.mi— c.0Vascularcontractionandintra—vascularmlcrothrombusformation mayOCCUrandresultlnsevereischemicinjury.Inthisstudy.we foundthatbothPGl2andTXA2remarkabllyincreasedattheearlv braininjurywithPGl2higherthanTXA2,totalSODdecreased. free .0dicalincreased,andbrainedemaaggravated. A1lthesefurther demonstratedthatpost—traumaticAA?PGsmetabolicdisorderwasan importantsecondarypathologicalchangeinbraininjury. 1ndomethacin1soneofnon—steroidanti—inflammatory.Itcanpotentlv inhibittheactivityofcyclooxygenaseandconsequentlvreducethe synthesisofPGs.RecentresearchesprovedthatitcoulddecreaseAA productionbydirectlyinhibitingphopholipaseA2actlvitv,andcould alsoreducemembranemobilitybyinhibitinglipidperoxidationl3l”.It hasbeenreportedthatindomethacinrelatedbrainedemaandlow pertusionfollowingischemiawereimprovedafterbeingpretreated withindomethacininexperimentalcats,whichwassimilart00xvgen freeradicalsclearingsubstancef6】inreducingischemiaextentand alleviatingincompleteischemlcbrainedema”】. Furthermore,Dre— treatmentwithindomethacincandecreasethemortalitv0fratswith braininjury.引.ManycurrentreportsindicatedthatI?.?indomethacin hasrapidreducingintracranialhypertensionandantifebrilePropertv withoutobviousi~ffluenceonCBFandoxygenmetabolismifapplied tOrtreatingintractableintracranialhypertensionandhyperthermia „.lJowingseverebraininjury,suggestingthatindomethacinhasa certaineffectonimprovingcerebralmicrocirculationand metabolism,andmayimprovetheprognosisofbraininiury.Its pharmacologicalmechanismmaybeexplainedasfollows[„】:firstlv. “domethacinhasdirectvasoconstrictiveeffectpresentedbyreducing CBFandintracranialpressure;secondly ,rati00fTXB,/ 6-keto—PGF~otincreasesbyinhibittingAA.PGsmetabolicpathwav , whichresultsinmicrovascularconstriction,decreasedCBFandin- tracranialpressure.Inourstudyweobservedthatsynthesis0fPGI, andTXA2wasremarkablyattenuatedbyindomethacinappliancefor braininjuryincats,resultinginthechangeofTXB2/6一keto—PGFlct anddecreasedfreeradicalproduction,suggestingthatindomethacin exertildluenceonsecondaryinjuryandhasacertaintheraDeutic effectonbraininjurybyregulatingtheimbalanceofPGl2andTXA,. „mprovingcerebrMmicrocirculation, anddecreasingfreeradicals production. Inconclusion,PGl2andTXA2remarkablyincreaseatearlvbraln injurywithPGl2higherthanTXA2.Inaddition,freeradicaIincn?ses 234ISSN1671—5926CN21—1470/R/[com中国临床康复2005笙旦! 旦笙!鲞笙塑 andbrainedemaOccurs,restulinginseverebrainin? jury.Indomethacincansignificantlyattenuatethepost—traumatic productionofPGI2andTXA2,regulatetheimbalanceofPG%/TX. A2,decreasefreeradicalproduction,andthereforeplayabeneficial roleinimprovingtheoutcomeofthesecondarybraininjury. REFERENCES 1ShohamiE.ShapiraY.SidiA.eta1.Headinjuryinducesincreasedprostaglandin svn【hesisinratbrainJCerebBloodFlowMetab1987;7:58—63 2KontosHA.WeIEPSuperoxideproductioninexperimentalbraininjuryJ 7 Nettrosttrg1986;64:803— 3HarriganMR.TutejaS,NeudeckBL.1ndomethacininthemanagementofele— vatedintracranialpressure:areviewJNeurotrauma1997;14:637—5O 4TanYF.LiYH.LinYJ.Animalmodelofgradedmechanicalbraininjuryin cats.ZhonghuaChuangshangZazhi(中华创伤杂志)2000;16(2):1OO一2 5TanZG.ChaiZJ.FengZY.Influenceofjndomethacinonfreeradicalreactionsin braintissues0frabbitswithbraininjuryHenanYikeDaxueXuebao(河南医 科 大学)2001;36(1):48—5O 6WeiEP.RontosHA.DietrichWD,eta1.inhibitionbyfreeradicalscavengers andbycyclooxygenaseinhibitorsofpialarteriolarabnormalitiesfromconcussive braininiuryincatsCircRes1981:48:95—1O3 7JohshitaH.AsanoT.HanamuraT.eta1.E? ctofindomethacinandafreeradi— calscavengeroncerebralbloodflowandedemaaftercerebralarteryocclusion in catsStroke1989?:20:788—94 8KimHJ.LevasseurJE.PattersonJLJr.eta1.E珏ctofindomethacinpretreatment 7 onacutemortalityinexperimentalbraininjury.JNeurosurg1989:71:565—2 9JensenK.OhrstromJ.ColdGE,eta1.Theeffectsofindomethacinonintracra nial pressure.cerebralbloodflowandcerebralmetabolisminpatentswithsevereh ead injuryandintracarialhypertension.ActaNeurochirfn)1991;1O8:116—21 脑损伤后早期前列腺素的变化及消炎痛的 干预作用? 谭源福r,李耀华(r广西医科大学第一附属医院神经外科,广西壮族自 治区南宁市530021;东南大学医学院附属中大医院脑外科,江苏省 南京市210000) 谭源福?男,1963年生湖南省株洲县人,汉族,1999年湖南医科大学 毕业,博士,教授,主要从事创伤性脑损伤的研究. 摘要 背景:颅脑损伤诱发的花生四烯酸代谢瀑布过程中产生的前列腺素类 和氧自由基的增加是其重要的一方面,消炎痛能强烈抑制环氧化酶 活 性,减少前列腺素类合成,并可能减少氧自由基的增加,从而可能具有 减轻脑损伤作用. 目的:观察脑损伤后早期前列腺素的变化及消炎痛对其的干预作用,探 讨其作用机制. :以实验动物为研究对象,随机对照实验研究 单位:一所大学医院的神经外科和一所大学医院的脑外科. 材料:实验于2000—03/09在东南大学医学院神经外科实验室完成.将 36只杂种猫,随机分为正常对照组,脑损伤组和消炎痛干预组3组,每 组12只. 干预:脑创伤按分级机械脑损伤实验动物模型制作,取中度脑损伤水平 进行研究.伤后6h测定脑静脉血中前列腺环素(PGI:)和血栓素(TXA) 的最终分解产物6一酮一前列腺素FIa(6一keto—PGF.”)和血栓烷素B2 (TXB),脑组织总超氧化物歧化酶(SOD)及脑含水量. 主要观察指标:6.keto.PGF.0l,TXB!,SOD含量和脑含水量测定 结果:猫脑损伤后早期脑静脉中6-keto.PGF.”和TXB_,均明显增加[由 (0.057?0.010)g/L增至(0.264?0.126)g/L,由(0.060?0.012)g/L 增至(0.134?0.048)g/L,6.keto.PGF1”增幅大于TXB,TXB/ 6-keto.PGF.”比值下降(由1.052?0.145降为0.545?0.184),脑含水量 增加[由(77.39?0.36)%增至(78.06?0.4l%)],同时脑组织总SOD明 显降低[由(94.869?5.418)Ixkat/g降至(54.368?3.417)Ixkat/g](P <0.01);消炎痛干预组与脑损伤组比较,6-keto.PGF?”和TXB!明显降 低,与正常对照组接近,而总SOD则有增加[(54.368?3.417)Ixkat/g 增至(81.433?7.268)Ixkat/g】(P<0.O1),脑含水量略降低,但无统 计学意义(P>0.1). 结论:猫脑损伤后早期PGIz和TXA!增加,并伴随自由基产生,由此加 重脑损害.消炎痛通过调节脑损伤后PGT/TXAz失衡,减少自由基产 生,有助于减轻脑创伤后继发性脑损害. 主题词:脑损伤;前列腺素;自由基;脑水肿;吲哚美辛;猫 中图分类号:R743文献码:A文章编号:1671—5926(2005)05—0232—03 谭源福,李耀华.脑损伤后早期前列腺素的变化及消炎痛的干预作用IJI中国 临床康复,2005,9(5l:232—41wwwzglckfcornl (EditedbyGuLJ/SunSG/JiH/XiaoXL) ? BAslCREsEARCH? Relationshipbetween(TTTTA)ngenepolymorphisminthe ap0lip0pr0tein(a)5?controlregionandatherosclerotic cerebralinfarctioninHannationalityofHubeiarea? HuBo,ZhouXin,LiZhao—xia,HongOuo?qiang,LuoMin—qi.ZhuZhen— yu HuBO,I.iZhao—xia,HongGuo—qiang,LuoMin—qi,DepartmentofClini cal Laboratory,ThirdAffiliatedHospitalofSunYat—senUniversity.Guangzho u 5l0630.GuangdongProvince.China ZhouXin,DepartmentofClinicalLaboratory.CentralSouthHospita1.Wuhan University,Wuchang43007l,HubeiProvince,China ZhuZhen—yu,DepartmentofBiochemistry,BasicMedicalCollege, Sun Yat—senUniversity,Guangzhou510089,GuangdongProvince,China HuBO?,Male,HanNationality.Borninl970inWuhanCitv.Hubei Province,China,StudyinginSunYat—senUniversityfordoctorate.Attending physician.Researchdirection:lipoproteinandcardiovasculardisease. hubo—bo@2lan.COB Telephone:+86—20—85516867Ext.3057 Suppor~dby:ScientificResearchStartingFoundationofSunYat..senU. nlversityofMedicalScience.No.A503 Received:2004一O7—28Accepted:2004一II一16f09/SL) Abstract BACKGROUND:Apolipoprotein(a)[Apo(a)]playssomeroleinpromot— ingtheformationofatheroscleroticplaque,andcontainspentanucleotide repeats(PNR),whichhasakeyvalueingenicresearchandinforecaston theincreasedriskofearlyatherosclerosiscerebralinfarction(ACI).Butthe relationshipbetweenACIandApo(a)PNRindifferentracesneedstobe furtheri?